Regulatory Issues
•
•
•
•
•
•
•
•
•
•
•
•
•
Introduction to the Regulatory Approval Process; Overview of the FDA
Investigational New Drug Application (IND); Summary of regulations and guidelines
Introduction of cGMP's/principles of validation
Introduction to QA/QC principles
Good Laboratory Practice (GLP) compliance
Pre-clinical testing for biotechnology products; safety and toxicology
Clinical stages, design of clinical trials and protocols, evaluation of clinical data
Regulatory Filings: Biological License Application (BLA)
Pre-approval inspections
Team Biologics
International regulatory status for biotechnology products; WHO, Japan, and the
EC/CPMP application
International Conference on Harmonization (ICH) update
Regulatory considerations for gene therapy and transgenic products
FDA Structure / Organization
FDA Structure / Organization
Food and Drug
Administration
Office of
Combination
Products
Center for Veterinary
Devices
National Center for
Toxicological Research
Center for Biologics
Evaluation and Research
Center for Food Safety and
Applied Nutrition
Center for Devices and
Radiological Health
Center for Drug Evaluation
and Research
CDRH Offices
Office of Device
Evaluation
Office of
Surveillance
& Biometrics
Office
of
Compliance
Office of In-Vitro
Diagnostic
Devices & Safety
Center for Devices and
Radiological Health
Office of
Science &
Technology
Office of Health
& Industry
Programs
FDA's Three Key Development Roles:
• "Gatekeeper" to the marketplace -- the new
drug approval process
• "Cop on the beat" or "Enforcer" -- ensuring
quality compliance via inspection and
enforcement actions (e.g. criminal charges)
• "Sentinel" of Safety Concerns - during
development and post-approval
FDA regulation of medical products
• Among the products that FDA regulates are
three categories of diagnostic, preventative, or
therapeutic products:
– Drugs
– Biologics
– Medical devices
6
The Approval Gate …
• Preliminary Considerations -- Determining the
Regulatory Status of the product
– Is it a "drug", "device" or "biologic"?
•
Drug:
– described in USP (United States Pharmacopeia) or
– intended (via labeling)
» to affect the body of man or other animals
» to be used in the diagnosis, cure, mitigation, treatment or
prevention of disease in man or other animals
The Approval Gate …
• Regulatory Status of the product - con'd…
– Is it a "drug", "device" or "biologic"?
•
Device: defined as involving: "instrument, apparatus, implement,
machine, contrivance, implant, in vitro reagent, or "similar or
related article including any component, part or accessory."
–
–
–
in USP/NF (the National Formulary) or
intended to be used in diagnosis … cure, mitigation, treatment or prevention
of disease or other conditions
intended to affect the body of man
The Approval Gate …
• Regulatory Status of the product - con'd…
– Is it a "drug", "device" or "biologic"?
•
Thus -- device definition can capture products that resemble drugs
if they do not achieve their result via being metabolized in the
body or via chemical action within or on the body -- regulated by
FDA Center for Devices & Radiological Health (CDRH)
–
Examples of "drug-like" devices:
» Ultrasound contrast media
» Contact lens solutions
The Approval Gate …
• Regulatory Status of the product - con'd…
– Is it a "drug", "device" or "biologic"?
•
Biologic -–
–
–
•
Generally, if derived from human or animal tissue;
used to be regulated by FDA Center for Biologics (CBER) using approval
standards similar to CDER
therapeutic biotech products going to CDER
» vaccines – remain behind
NOTE: "true" biotech products usually are biologics
The Approval Gate …
• Regulatory Status of the product - con'd…
– Is it a "drug", "device" or "biologic"?
– OR BOTH??
– "Combination" or "hybrid" products -•
•
•
are regulated per their "primary mode of action" -but this may be difficult to discern -- get clarification very early as
will impact FDA Center you deal with
can request in writing -- under FDAMA § 416, FDA can't later
change its mind w/o your consent or public health reasons exist
The Approval Gate …
• Regulatory Status of the product - con'd…
– What type of submission is needed to get FDA
approval or clearance?
– Drugs:
•
•
•
•
Full New Drug Application (NDA)
505(b)(2) NDA or "Paper NDA"
Abbreviated New Drug Application
The OTC Drug route -- Abreva (Avanir/SKB)
– NDA
– OTC Review monograph change
The Approval Gate …
• Regulatory Status of the product - con'd…
– What type of submission is needed to get FDA
approval or clearance?
– Devices:
• Premarket Approval Application (PMA) -- clinical studies
will be needed
• Premarket Notification under § 510k -- clinical studies MAY
be needed (or wanted)
The Approval Gate …
• Regulatory Status of the product - con'd…
– What type of submission is needed to get FDA
approval or clearance?
– Biologics
• Biologic License Application (BLA)
• no generic versions now possible – may change …
The Approval Gate …
• Regulatory Status of the product - con'd…
– What quantity and quality of data will be demanded
by FDA to show safety & effectiveness?
– Will vary -- FDA has extensive discretion here
– Key task -- try to get clarity as soon as possible in the
process -- Ways to do so:
•
•
Pre-IND meeting -- encouraged by FDA prior to start of human
clinicals
End of Phase 2 Meeting - also encouraged -- here's where you want
to "lock" them in
Overview of Typical Pharmaceutical Product
Development
IP
Marketing
Research
PreClinical
Work
Cost:1
F
I
L
I
N
G
Preclinical to Phase II - Approximately 1-7 million
Marketing Plan
Product
Launch
A
P
P
R
O
V
A
L
Clinical
Studies
Phase III - 2 - 8 million
V
A
L
I
D
A
T
I
O
N
Registration
Validation
Validation Batches - Product Costs
and Labor X 3 to 5 batches
Commercial
Production
Total Costs = 10-25 million USD
Production Start Up Costs based on Contract or Facility
Total Time = 4.5 - 7.5 years
Time:2,3
Preclinical to Completed Clinicals - 3-5 years
FDA Approval - 13.5 months 3
Validation and Production Launch - 6-18 months
1
In 2000 Dollars - Estimates by the National Cancer Institute for all new pharmaceutical. Estimate does not consider R&D costs that are not associated with the development of the drug in question. Most drug companies use a system of cost estimates that
includes the valuation of money if it had been invested andthe cost of drug development not approved by the FDA. Most studies conclude that the rate of commercialization success to be 1:5000. How Much does it cost to develop a new drug - James Love Consumer Project on
Technology http://www.cptech.org April 2, 2000
2 Drug Approval Overregulation, MR Ward - CATO Regulation - http://www.cato.org/pubs/regulation/reg15n4e.htm
3 New York Times - November 8 1995
16
Welcome to the Jungle
Pre Clinical
Work
Stable
Clinical
Trials
Filing
GO
Registration
Validation
Approval
FAIL
Unstable
Proof of
Concept
FAIL
Effective
Effective
Ineffective
GO
FAIL
Ineffective
Safe
Max.
Energy
Batch
Phase
II
FAIL
Effective
Ineffective
GO
Inferior
FAIL
Toxic
GO
Definition
Micro
FAIL
FAIL
Grows Bugs
Passes ID
& Description
GO
Chemistry
FAIL
Degradants
& Impurities
Ineffective
Effective
Failure is Unlikely
Nominal
Batch
Clinical Report
Reformulation
Egg
START OVER
Sell
Product
GO
FAIL
GO
Launch
Quarantine
Product
FDA STUDIES
& Aseptic
Phase
III
Death of
Product
Antimicrobial
Fill Sales &
Warehouse Pipeline
GO
RESET ALL PARAMETERS
FAIL
Toxicology
Launch
Ad Campaign
FAIL
Efficacy
GO
GO
GO
Animal
Commercial
Production
Scale Up
Production
Min.
Energy
Batch
Phase
I
Stability
Pre Approval
Inspection
Phase
IV
Formula Improvement
Geriatric or Pediatric
Validation Report
Stability Testing
Drug Interaction
17
Define LT & Side Effects
And the next step…
• You’ve got the device or drug okayed—now
you have to manufacture it…
GMPs
• Current good manufacturing practices (GMPs) are
the methods by which manufacturers, holders, and
transporters of drugs, biologics, or devices assure
that every product that they make, hold, or transport
is, and continues to be until it is used, safe and
effective.
• Failure to comply with GMPs (and for devices, failure
to comply with the quality system regulations) makes
a product “adulterated” and its distribution or sale
illegal.
19
The Early Beginnings
• 1900s house-calls
• Home remedies, ointments and
“miracle elixirs”
• Entertainment and music
• No regulations until 1902
Fig. 1. Animation of ancient medicine show
Public Involvement
• 1905 - The Jungle by Upton
Sinclair
• Exposure of unsanitary
conditions in meat packing
plants
• Public awareness and
involvement
Fig. 2. The Jungle by Upton Sinclair
• Pure Food and Drug Act
• False labeling became illegal
Fig. 3. 1906 Meat processing plant
What is GMP?
• Good Manufacturing
Practice is a set of
regulations, codes, and
guidelines for the
manufacture of drug
substances and drug
products, medical devices,
in vivo and in vitro
diagnostic products, and
foods.
Fig.4 GMP handbooks for every industry
Good Manufacturing Practices
Worldwide Enforcement
• Good Manufacturing Practices are enforced in the United
States by the FDA
• In the United Kingdom by the Medicines and Healthcare
Products Regulatory Agency
• GMPs are enforced in Australia by the Therapeutically Goods
Administration
• In India by the Ministry of Health, multinational and/or
foreign enterprises
• Many underdeveloped countries lack GMPs
1941 Initiation of GMP
• Sulfathiaziole tablets
contaminated with phenobarbital
• 1941 - 300 people died/injured
• FDA to enforce and revise
manufacturing and quality control
requirements
• 1941 - GMP is born
Fig. 5 1906 Certificate of Purity signed by
doctor
1962 Kefauver-Harris Drug
Amendments
• Thalidomide tragedy
• Thousands of children born
with birth defects due to
adverse drug reactions of
morning sickness pill taken by
mothers
• Strengthen FDA’s regulations
regarding experimentation on
humans and proposed new way
how drugs are approved and
regulated
• “Proof of efficacy” law
1976 Medical Device Amendments
• 1972 and 1973 -Pacemaker
failures reported
• 1975 - hearing-Dalkon
Shield intrauterine device
caused thousands of
injuries
• Class I, II and III medical
devices – based on degree
of control necessary to be
safe and effective
Fig.7 President Gerald Ford signs the
Medical Device Amendments
1980 Infant Formula Act
• 1978 - major manufacturer of
infant formula reformulated
two of its soy products
• 1979 - Infants diagnosed with
hypochloremic metabolic
alkalosis
• Greater regulatory control
over the formulation and
production of infant formula
• Modification of industry’s and
FDA’s recall procedures
Fig.8 Parody on Infant Formula Act
Part 211 –Selected cGMP For Finished
Pharmaceuticals
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Subpart A-General Provisions
Subpart B-Organization and Personnel
211.22 Responsibilities of quality control
unit.
211.25 Personnel Qualifications.
211.28 Personnel responsibilities.
Subpart C-Buildings and Facilities
211.46 Ventilation, air filtration, air heating
and cooling.
211.58 Maintenance
Subpart D-Equipment
211.63 Equipment design, size, and location.
211.65 Equipment construction.
211.67 Equipment cleaning and
maintenance.
211.68 Automatic, mechanical, and
electronic equipment.
211.72 Filters.
•
•
•
•
•
Subpart E-Control of Components and Drug
Product Containers and Closures
211.80 General requirements.
211.82 Receipt and storage of untested
components, drug product containers, and
closures.
211.84 Testing and approval or rejection of
components, drug product containers, and
closures.
211.86 Use of approved components, drug
product containers, and closures.
Subpart F-Production and Process Controls
211.100 Written procedures; deviations.
211.101 Charge-in of components.
211.103 Calculation of yield.
211.105 Equipment identification.
•
..............
•
•
•
•
§ 211.25 Personnel qualifications
•
(a) Each person engaged in the manufacture, processing, packing, or holding of a drug product
shall have education, training, and experience, or any combination thereof, to enable that person
to perform the assigned functions. Training shall be in the particular operations that the
employee performs and in current good manufacturing practice (including the current good
manufacturing practice regulations in this chapter and written procedures required by these
regulations) as they relate to the employee's functions. Training in current good manufacturing
practice shall be conducted by qualified individuals on a continuing basis and with sufficient
frequency to assure that employees remain familiar with CGMP requirements applicable to them.
•
(b) Each person responsible for supervising the manufacture, processing, packing, or holding of a
drug product shall have the education, training, and experience, or any combination thereof, to
perform assigned functions in such a manner as to provide assurance that the drug product has
the safety, identity, strength, quality, and purity that it purports or is represented to possess.
•
(c) There shall be an adequate number of qualified personnel to perform and supervise the
manufacture, processing, packing, or holding of each drug product.
Quality Assurance vs. Quality
Control
Quality Assurance
An overall
management plan to
guarantee the
integrity of data
(The “system”)
Quality Control
A series of
analytical
measurements used
to assess the
quality of the
analytical data
(The “tools”)
True Value vs. Measured Value
True Value
The known,
accepted value of
a quantifiable
property
Measured Value
The result of an
individual’s
measurement of
a quantifiable
property
Accuracy vs. Precision
Accuracy
Precision
How well a
measurement agrees
with an accepted
value
How well a series of
measurements agree
with each other
Systematic vs.
Random Errors
Systematic Error
Avoidable error due
to controllable
variables in a
measurement.
Random Errors
Unavoidable errors
that are always
present in any
measurement.
Impossible to
eliminate
Quality Control Measures
•
•
•
•
•
•
Standards and Calibration
Blanks
Recovery Studies
Precision and Accuracy Studies
Method Detection Limits
State Laws
Standards and Calibration
•
•
•
•
•
•
Prepared vs. Purchased Standard
Signals: Peak Area, Beer’s Law
Calibration Curves
Continuing Calibration Checks
Internal Standards
Performance Testing
Calibration Curves
Graphical representation of the
relationship between:
• The concentration of the analyte
and
• The analytical signal
Calibration Curve for DDT
Peak area x 10
6
500
400
y = 9.3005x + 4.3313
300
2
200
R = 0.9989
100
0
0
10
20
30
40
Parts per trillion DDT
50
60
Continuing Calibration
Verification
• Many methods don’t require that
daily calibration curves are
prepared
• A “calibration verification” is
analyzed with each batch of samples
Sample Batch
• 10 - 20 samples (method defined)
or less
• Same matrix
• Same sample prep and analysis
• Contains a full set of
QC samples
Internal Standards
• A compound chemically similar to the
analyte
• Not expected to be present in the
sample
• Cannot interfere in the analysis
• Added to the calibration standards
and to the samples in identical
amounts
Internal Standards
• Refines the calibration process
• Analytical signals for calibration
standards are compared to those for
internal standards
• Eliminates differences in random and
systematic errors between samples
and standards
Performance Testing
Blind samples submitted to
laboratories
?
?
Labs must periodically analyze with acceptable results in order to
maintain accreditation
?
Blanks, Blanks, Blanks
• Laboratory Reagent Blanks
• Instrument Blanks
• Field Reagent Blanks
• Trip Blanks
Laboratory Reagent Blanks
• Contains every reagent used in the
analysis
• Is subjected to all analytical
procedures
• Must give signal below detection limit
• Most methods require one with every
batch
Instrument Blank
• A clean sample (e.g., distilled water)
processed through the instrumental
steps of the measurement process;
used to determine instrument
contamination
Field Reagent Blanks
• Prepared in the lab, taken to the
field
• Opened at the sampling site, exposed to sampling equipment, returned to the
lab.
Trip Blanks
• Prepared in the lab, taken to the
field
• Not opened
• Returned to the lab
• Not always required in EPA methods
Recovery Studies
• Matrix Spikes
• Laboratory Control Samples
• Surrogates
Matrix Spikes
• Sample spiked with a known
amount of analyte
• Subjected to all sample prep and
analytical procedures
• Determines the effect of the matrix
on analyte recovery
• Normally one per batch
Laboratory Control Sample
• Analyte spiked into reagent water
• Subjected to all sample prep and
analytical procedures
Precision and Accuracy
• Required for initial certification and
annually thereafter
• A series of four laboratory control
samples
• Must meet accuracy (recovery) and
precision (standard deviation)
requirements, often in method
Method Detection Limit
“The minimum concentration of a
substance that can be measured and
reported with 99% confidence that the
analyte concentration is greater than zero”
Method Detection Limit
• MDLs are determined according to
40 CFR, part 136, Appendix B
• Seven replicate laboratory control
samples, analyzed for precision
Method Detection Limit
• Must be performed initially for
certification
• Must meet criteria specified in
method
• Must be performed with change in
instrumentation or test method
• Annually with ELCP (Environmental
Laboratory Certification Program)
State Laws
• Each state has laws governing laboratories and
their personnel.